Substance abusers with other psychiatric disorders pose complex therapeutic challenges. The importance of these associations is most telling among injection drug users (IDUs) in whom drug use conveys the risk of acquiring human immunodeficiency virus (HIV) and other infectious diseases. The objective of this research is to investigate ways of treating depressive symptoms among IDUs enrolled in a needle exchange program, a population characterized by high rates of depressive symptoms and HIV risk behaviors. The long-term objective of this programmatic body of research is to investigate ways of reducing HIV risk behaviors among IDUs. In this proposed randomized trial, a 2-group (antidepressant medication plus cognitive-behavioral therapy (CBT) vs. treatment- as-usual)design will be used to determine whether the intervention is effective in reducing HIV risk behaviors. The treatment group will receive 12-weeks of combined CBT plus antidepressant medication while subjects in the treatment-as- usual condition will be referred to community mental health treatment sites. Subjects will be interviewed at 3-, 6- and 9- months following the start of the intervention. Primary outcome variables include HIV risk behaviors (injection drug use, unprotected sex) as measured by the HIV Risk Assessment Battery (RAB) and the TCU AIDS Risk Assessment (TCU/ARA). This study will extend previous research by evaluating the use of a combined CBT plus antidepressant medication intervention with IDUs enrolled in a needle exchange program. The co-occurrence of depression with injection drug use in a population with traditionally poor linkage to mental health care, an enormous burden of illness, and high HIV transmission risk, compels health care providers and policy makers to explore innovative approaches to improve the health of this group.